Dysregulation of Airway and Systemic Interferon Responses Promote Asthma Exacerbations in Urban Children

Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need.

Objective: To identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation.

Methods: 208 urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to two cold illnesses. Exacerbation illnesses (Ex+), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex-). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex+ and Ex- illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables.

Results: 106 participants were evaluated during 154 colds. There was greater up-regulation of differentially expressed interferon genes during Ex+ illnesses compared to Ex-. Ex+ illnesses had greater average and steeper rise in interferon expression. Within three days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal:adjustedR²=0.48, p=0.015; blood:adjustedR²=0.22, p=0.013) and interferon expression was negatively associated with FEV₁ percent predicted (nasal:β=-0.010, p=0.048; blood:β=-0.008, p=0.023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses and greater increase in interferon expression during viral colds (nasal:β=-0.80, p<0.0001; blood:β=-0.75, p<0.0001).

Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater up-regulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.